Insulin is an important hormone in maintaining glucose homeostasis by coordinating the glucose absorption in peripheral tissues and hepatic glucose production. In insulin sensitive tissues, insulin triggers the exocytosis of glucose transporter, enhances the expression of glycolytic enzymes and suppresses the enzymes involved in gluconeogesis. The action of insulin is initiated by binding to its cognate receptor (IR) and activation of the receptor's intrinsic protein tyrosine kinase activity, resulting in the phosphorylation of tyrosine residues located in the cytoplasmic domain. The activated receptor, in turn, recruits and phosphorylates a panel of substrate molecules including IRS-1 and IRS-2. Tyrosine phosphorylated IRS-1/2 recruit the PI 3-kinase to the plasma membrane, where it generates the essential lipid second messenger PIP3, an essential lipid second messenger, which subsequently activates PDK1, PKB/Akt, and PK Cζ and λ isoforms etc. One of the major targets of activated Akt is GSK-3. Akt phosphorylation of GSK leads to its inactivation and glycogen synthesis upregulation. Akt also regulates the insulin-stimulated translocation of the glucose transporter GLUT-4 to the plasma membrane, resulting in increased glucose uptake. Impairment of components in the pathway often leads to disorders like type 2 diabetes (T2D), which is characterized in chronic hyperglycemia and progressive f3-cell failure with insufficient insulin output.
Diabetes mellitus (DM) is a metabolic disease with increasing prevalence. Since the decline of pancreatic β-cell function is the major reason for all type 1 diabetes (T1D) and exacerbate type 2 diabetes (T2D) patients, maintaining sufficient circulating insulin thus represents the primary goal in treating DM. Impaired insulin secretion (β-cell), increased hepatic glucose production (liver), and decreased peripheral (muscle) glucose utilization constitute the traditional primary defects responsible for the development and progression of type 2 diabetes mellitus. Currently, the management of type 2 diabetes focuses on glucose control via lowering of blood glucose and hemoglobin Alc(lcHbAlc) with various pharmacological agents. Metformin and the thiazolidinediones (TZDs) are insulin sensitizers that inhibit the increased rate of hepatic gluconeogenesis responsible for the elevated rate of basal hepatic glucose production (HGP) in patients with type 2 diabetes. In adipose tissue, the TZDs also are insulin sensitizers, exerting a potent antilipolytic effect. See Gastaldelli et al., J Clin Endocrinol Metab 91:806-812, 2006 and Gastaldelli et al., Am J Physiol Endocrinol Metab 292:E871-883, 2007. Additionally, the TZDs have been shown to improve and preserve β-cell function. In recent years, treatment strategies have focused on the development of novel therapeutic options that affect many of against the defects contributing to T2D and provide a durable glucose control through a blunting of disease progression. Similar to the patients with T1D, insulin therapy is now recognized as a customary treatment in advanced T2D patients when glycemic control is suboptimal. Discard of its relative effectiveness of glycemic control in T2D patients, subcutaneous insulin injection has suffered from drawbacks including, tissue irritation, infection on injection sites, inconvenience and variation of insulin delivery rate. Therefore, the identification of orally active small molecules that are able to mimic insulin's effect might lead to a better therapy for both DM patients.
Wilcke et al., WO 2008/008033 provides napthoquinones. It also refers to the treatment and control of diabetes, insulin resistance, and hyperglycemia. However, there is a need to identify improved methods and compositions.